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1.  Association between CYP1B1 Gene Polymorphisms and Risk Factors and Susceptibility to Laryngeal Cancer 
Background
The aim of this study was to investigate the association between polymorphism of the cytochrome P450 1B1 (CYP1B1) gene, a metabolic enzyme gene, and the susceptibility to laryngeal cancer among the Chinese Han population.
Material/Methods
In a case-control study, we investigated polymorphisms in the CYP1B1 gene (rs10012, rs1056827, and rs1056836) with a real-time quantitative polymerase chain reaction (PCR) assay (TaqMan). The study was conducted with 300 Chinese Han patients with laryngeal cancer and 300 healthy Chinese Han subjects in a control group. We also studied the interactions between genetic polymorphism and risk factors such as smoking and alcohol consumption in the pathogenesis of laryngeal cancer.
Results
There were statistically significant differences in the distributions of the rs1056827 and rs1056836 genotypes between the 2 groups. Regarding rs1056827, carriers of the T allele had a significantly higher risk of laryngeal cancer than the G-allele carriers (OR=1.4339, 95% CI: 1.1268–1.8247; P=0.0034). The difference was still statistically significant after adjusting for factors such as age, sex, smoking, and drinking (adjusted OR=1.743, 95% CI: 1.124–3.743, P<0.001). However, regarding rs1056836, the G allele carriers had a significantly lower risk of laryngeal cancer than the C allele carriers (OR=0.5557, 95% CI: 0.3787–0.8154; P=0.0027). The difference was statistically significant even after adjusting for factors such as age, sex, smoking, and drinking (adjusted OR=0.5641, 95% CI: 0.3212–0.8121, P=0.001). Subjects who carry the C-T-C haplotype have a significantly increased incidence of laryngeal cancer. We also found that CYP1B1 rs1056827 polymorphism had synergistic effects with smoking or alcohol consumption regarding the risk of laryngeal cancer.
Conclusions
CYP1B1 gene polymorphism is closely related to the onset of laryngeal cancer. There is a mutually synergistic effect between smoking, alcohol consumption, and CYP1B1 gene polymorphisms regarding laryngeal cancer.
doi:10.12659/MSM.893084
PMCID: PMC4307736  PMID: 25619313
Laryngeal Neoplasms; Polymorphism, Single Nucleotide; Steroid 11-beta-Hydroxylase
2.  5-Fluorouracil Chemotherapy of Gastric Cancer Generates Residual Cells with Properties of Cancer Stem Cells 
Background: 5-Fluorouracil (5Fu) chemotherapy is the first treatment of choice for advanced gastric cancer (GC), but its effectiveness is limited by drug resistance. Emerging evidence suggests that the existence of cancer stem cells (CSCs) contributes to chemoresistance. The aim of the present study was to determine whether 5Fu chemotherapy generates residual cells with CSC-like properties in GC. Methods: Human GC cell lines, SGC7901 and AGS, were exposed to increasing 5Fu concentrations. The residual cells were assessed for both chemosensitivity and CSC-like properties. B lymphoma Mo-MLV insertion region 1 (BMI1), a putative CSC protein, was analyzed by immunohistochemical staining and subjected to pairwise comparison in GC tissues treated with or without neoadjuvant 5Fu-based chemotherapy. The correlation between BMI1 expression and recurrence-free survival in GC patients who received 5Fu-based neoadjuvant chemotherapy was then examined. Results: The residual cells exhibited 5Fu chemoresistance. These 5Fu-resistant cells displayed some CSC features, such as a high percentage of quiescent cells, increased self-renewal ability and tumorigenicity. The 5Fu-resistant cells were also enriched with cells expressing cluster of differentiation (CD)133+, CD326+ and CD44+CD24-. Moreover, the BMI1 gene was overexpressed in 5Fu-resistant cells, and BMI1 knockdown effectively reversed chemoresistance. The BMI1 protein was highly expressed consistently in the remaining GC tissues after 5Fu-based neoadjuvant chemotherapy, and BMI1 levels were correlated positively with recurrence-free survival in GC patients who received 5Fu-based neoadjuvant chemotherapy. Conclusions: Our data provided molecular evidence illustrating that 5Fu chemotherapy in GC resulted in acquisition of CSC-like properties. Moreover, enhanced BMI1 expression contributed to 5Fu resistance and may serve as a potential therapeutic target to reverse chemoresistance in GC patients.
doi:10.7150/ijbs.10248
PMCID: PMC4323368
Gastric cancer; 5-Fluorouracil (5Fu); Chemoresistance; Cancer stem cells
3.  Sevoflurane Postconditioning Protects Rat Hearts against Ischemia-Reperfusion Injury via the Activation of PI3K/AKT/mTOR Signaling 
Scientific Reports  2014;4:7317.
Phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway plays a key role in myocardial ischemia-reperfusion (I/R) injury. Mammalian target of rapamycin (mTOR), a downstream target of PI3K/AKT signaling, is necessary and sufficient to protect the heart from I/R injury. Inhaled anesthetic sevoflurane is widely used in cardiac surgeries because its induction and recovery are faster and smoother than other inhaled anesthetics. Sevoflurane proved capable of inducing postconditioning effects in the myocardium. However, the underlying molecular mechanisms for sevoflurane-induced postconditioning (SPC) were largely unclear. In the present study, we demonstrated that SPC protects myocardium from I/R injury with narrowed cardiac infarct focus, increased ATP content, and decreased cardiomyocyte apoptosis, which are mainly due to the activation of PI3K/AKT/mTOR signaling and the protection of mitochondrial energy metabolism. Application of dactolisib (BEZ235), a PI3K/mTOR dual inhibitor, abolishes the up-regulation of pho-AKT, pho-GSK, pho-mTOR, and pho-p70s6k induced by SPC, hence abrogating the anti-apoptotic effect of sevoflurane and reducing SPC-mediated protection of heart from I/R injury. As such, this study proved that PI3K/AKT/mTOR pathway plays an important role in SPC induced cardiac protection against I/R injury.
doi:10.1038/srep07317
PMCID: PMC4255182  PMID: 25471136
4.  Intra-Articular Adhesion Reduction after Knee Surgery in Rabbits by Calcium Channel Blockers 
Background
Intra-articular adhesion after knee surgery is a common and serious complication that presents a challenging problem for orthopedic surgeons. Verapamil (VP), a widely used calcium channel blocker, has been shown to prevent synthesis/secretion of extracellular matrix molecules. The object of this study was to investigate the effects of VP on the prevention of joint adhesion in post-surgery rabbits.
Material/Methods
A controlled double-blinded study was conducted in 40 healthy New Zealand white rabbits divided randomly into 4 groups according to the treatment method, with 10 in each group: 1) 1 mg/ml VP treatment group; 2) 2.5 mg/ml VP treatment group; 3) 5 mg/ml VP treatment group; 4) control group. Rabbits underwent surgery through the medial parapatellar approach and both lateral sides and the medial of the femoral condyle were surgically exposed. After treatment, the surgical limbs were subjected to extra-articular knee-joint immobilization in the full flexed position employing Kirschner wires for 4 weeks.
Results
The knee surgery was successfully performed on all rabbits. The rabbits were killed 4 weeks post-operatively. The histological evaluation, hydroxyproline content, visual score, fibroblasts density, and vimentin expressional levels were conducted to assess the effect of VP on preventing joint adhesion.
Conclusions
In our rabbit model of knee surgery, intra-articular application of VP was able to decrease intra-articular adhesion formation after surgery. VP could prevent rabbit intra-articular adhesion in a dose-dependent manner and the highest concentration used in the study (5 mg/ml) proved to be the most effective.
doi:10.12659/MSM.892957
PMCID: PMC4259520  PMID: 25430622
Knee Joint; Rabbits; Tissue Adhesions; Verapamil
5.  A pilot study of angiogenin in heart failure with preserved ejection fraction: a novel potential biomarker for diagnosis and prognosis? 
Characteristics of heart failure with preserved ejection fraction (HFPEF) have not yet been fully understood. The objectives of this pilot study are to detect protein expression profile in the sera of HFPEF patients, and to identify potential biomarkers for the disease. Five hundred and seven proteins were detected in the sera of healthy volunteers and patients with either HFPEF or hypertension using antibody microarrays (three in each group). The results showed that the serum concentrations of 17 proteins (e.g. angiogenin, activin A and artemin) differed considerably between HFPEF and non-HFPEF patients (hypertensive patients and healthy controls), while a protein expression pattern distinct from that in non-HFPEF patients was associated with HFPEF patients. The up-regulation of angiogenin in both HFPEF patients with LVEF ≥50% (P = 0.004) and a subset of HFPEF patients with LVEF = 41–49% (P < 0.001) was further validated in 16 HFPEF patients and 16 healthy controls. Meanwhile, angiogenin distinguished HFPEF patients from controls with a mean area under the receiver operating characteristic curve of 0.88 (P < 0.001) and a diagnostic cut-off point of 426 ng/ml. Moreover, the angiogenin levels in HFPEF patients were positively correlated with Lg(N-terminal pro-B-type natriuretic peptide, NT-proBNP) (P < 0.001). In addition, high angiogenin level (≥426 ng/ml) was a predictor of all-cause death within a short-term follow-up duration, but not in the longer term of 36 months. This pilot study indicates that the aforementioned 17 potential biomarkers, such as angiogenin, may hold great promise for both diagnosis and prognosis assessment of HFPEF.
doi:10.1111/jcmm.12344
PMCID: PMC4224553  PMID: 25124701
heart failure with preserved ejection fraction; angiogenin; biomarker; proteomics
6.  Anti-proliferative of physcion 8-O-β-glucopyranoside isolated from Rumex japonicus Houtt. on A549 cell lines via inducing apoptosis and cell cycle arrest 
Background
Lung cancers are leading causes of cancer death, and Rumex japonicus has been traditionally used in folk medicine as anti-microorganic, anti-inflammatory and anti-tumor agents. This study was designed to investigate the anti-proliferative activity of physcion 8-O-β-glucopyranoside (PG) isolated from Rumex japonicus Houtt. on A549 cell lines.
Methods
In our present study, PG was isolated and identified from the ethanol extracts of R. japonicus. MTT method was used to evaluate the anti-proliferative activity of PG on A549 cell lines, and cell cycle distribution assay, apoptosis assay, and western blot analysis in vitro were used to explore the possible mechanisms.
Results
From the results of our present study, cell viability was obviously inhibited by PG, in a dose- and time-dependent manner. Our results also suggested that the anti-proliferative effect of PG was related to cell cycle arrest at the G2/M phase through repression of cdc2 and Cyclin B1 protein expression. In addition, the results of apoptosis assay and western blot analysis indicated that the anti-proliferative activity could be related to apoptosis via up-regulating the expressions of Bax, caspase-3 and caspase-7, and down-regulating the expressions of Bcl-2.
Conclusions
In conclusion, the PG has significant anti-proliferative activity on A549 cell lines, and the possible mechanism was related to cell cycle arrest at the G2/M phase, and apoptosis via the regulations of Bax, Bcl-2, and caspase-3 and caspase-7.
doi:10.1186/1472-6882-14-377
PMCID: PMC4201690  PMID: 25283233
Physcion 8-O-β-glucopyranoside; Rumex japonicus Houtt; Anti-proliferative activity; Apoptosis; Lung cancer
7.  Phase-pure iron pyrite nanocrystals for low-cost photodetectors 
Nanoscale Research Letters  2014;9(1):549.
Earth-abundant iron pyrite (FeS2) shows great potential as a light absorber for solar cells and photodetectors due to their high absorption coefficient (>105 cm-1). In this paper, high-quality phase-pure and single crystalline pyrite nanocrystals were synthesized via facile, low-cost, and environment friendly hydrothermal method. The molar ratio of sulphur to iron and the reaction time play a crucial role in determining the quality and morphology of FeS2 nanocrystals. X-ray diffraction and high-resolution transmission electron microscopy confirm that phase-pure and single crystalline pyrite nanocrystals can be synthesized with high sulphur to iron molar ratio and sufficient reaction time. For the first time, a crystalline nanogap pyrite photodetector with promising photocurrent and UV-visible photoresponse has been fabricated. This work further demonstrates a facile route to synthesize high-quality FeS2 nanomaterials and their potential in optoelectronic applications.
doi:10.1186/1556-276X-9-549
PMCID: PMC4194451  PMID: 25317102
Iron pyrite; Photodetector; Hydrothermal; Nanocrystal
8.  Frontolimbic atrophy is associated with agitation and aggression in mild cognitive impairment and Alzheimer's disease 
Background
The neuroanatomy of agitation and aggression in Alzheimer's disease is not well understood.
Methods
We analyzed 24 months of Alzheimer's Disease Neuroimaging Initiative data for patients with Alzheimer's disease, mild cognitive impairment-stable, and mild cognitive impairment-converter (n = 462) using the Neuropsychiatric Inventory Questionnaire Agitation and Aggression subscale. Magnetic resonance imaging regions of interest that correlated with Neuropsychiatric Inventory Questionnaire Agitation and Aggression subscale raw scores were included in mixed-model, repeated-measures analyses of agitation and aggression over time with age, sex, apolipoprotein E ε4 status, education, and Mini-Mental State Examination score as covariates.
Results
Neuropsychiatric Inventory Questionnaire Agitation and Aggression subscale scores worsened in patients with Alzheimer's disease and in mild cognitive impairment-converter (P <.05; trend for mild cognitive impairment, P =.0518). Greater agitation and aggression severity was associated with greater atrophy of frontal, insular, amygdala, cingulate, and hippocampal regions of interest (P < .05). Mini-Mental State Examination score was significant in mixed-effect model repeated measures only in mild cognitive impairment-converters for posterior regions of interest. Demographics and apolipoprotein ε4 were not associated with agitation and aggression.
Conclusions
Agitation and aggression in Alzheimer's disease and mild cognitive impairment is associated with neurodegeneration affecting the anterior salience network that may reduce capacity to process and regulate behaviors properly.
doi:10.1016/j.jalz.2012.10.005
PMCID: PMC3955297  PMID: 23253778
MRI; Agitation and aggression; Alzheimer's disease; Mild cognitive impairment; Frontolimbic; Salience network
9.  Association of pSTAT3-VEGF signaling pathway with peritumoral edema in newly diagnosed glioblastoma: an immunohistochemical study 
It is well recognized that peritumoral edema is vasogenic cerebral edema in malignant glioma, and vascular endothelial growth factor (VEGF) induced by phosphorylated signal transducer and activator of transcription factor 3 (pSTAT3) strongly contributes to tumor angiogenesis in glioblastoma. However, there is no study with regard to the correlation between pSTAT3 or VEGF and peritumoral edema. Such evidence may contribute to providing new targets for the management of peritumoral cerebral. In this study, newly diagnosed glioblastoma tissues from 84 patients were collected to investigate pSTAT3 and VEGF expression by immunohistochemistry, and peritumoral edema was detected by preoperative magnetic resonance imaging. We found that a significantly positive correlation emerged between VEGF and pSTAT3 expression (P = 0.000) in glioblastoma tissues, but they were not related to patient gender and age (P > 0.05); the expression of pSTAT3 and VEGF were associated with peritumoral edema extent (P = 0.005), but not with edema shape (P > 0.05). Therefore, the pSTAT3-VEGF signaling pathway, which is correlated with peritumoral edema extent, might be a regulatory mechanism in the course of peritumoral edema formation during glioblastoma tumorigenesis and progression, thereby suggesting that STAT3 inhibition might be helpful for alleviation of peritumoral cerebral edema.
PMCID: PMC4203232  PMID: 25337261
Glioblastoma; peritumoral edema; signal transducer and activator of transcription factor 3; phosphorylation; vascular endothelial growth factor
10.  Comparison of the clinical features and outcomes in two age-groups of elderly patients with atrial fibrillation 
Background
Atrial fibrillation (AF) disproportionately affects older adults. However, direct comparison of clinical features, medical therapy, and outcomes in AF patients aged 65–74 and ≥75 years is rare. The objective of the present study was to evaluate the differences in clinical characteristics and prognosis in these two age-groups of geriatric patients with AF.
Materials and methods
A total of 1,336 individuals aged ≥65 years from a Chinese AF registry were assessed in the present study: 570 were in the 65- to 74-year group, and 766 were in the ≥75-year group. Multivariable Cox hazards regression was performed to analyze the major adverse cardiac events (MACEs) between groups.
Results
In our population, the older group were more likely to have coronary artery disease, hypertension, previous stroke, cognitive disorder, or chronic obstructive pulmonary disease, and the 65- to 74-year group were more likely to have valvular heart disease, left ventricular systolic dysfunction, or sleep apnea. The older patients had 1.2-fold higher mean CHADS2 (congestive heart failure, hypertension, age ≥75 years, diabetes, stroke) scores, but less probability of being prescribed drugs. Compared with those aged 65–74 years, the older group had a higher risk of death (hazard ratio 2.881, 95% confidence interval 1.981–4.189; P<0.001) or MACE (hazard ratio 2.202, 95% confidence interval 1.646–2.945; P<0.001) at the 1-year follow-up. In multivariable Cox analyses, secondary AF diagnosis, a history of chronic obstructive pulmonary disease, and left ventricular systolic dysfunction were independent predictors of MACE in the older group.
Conclusion
Patients aged ≥75 years had a worse prognosis than those aged 65–74 years, and were associated with a higher risk of both death and MACE.
doi:10.2147/CIA.S67123
PMCID: PMC4136954  PMID: 25143720
atrial fibrillation; geriatric patients; mortality; major adverse cardiac events (MACE)
11.  LEAFY Controls Auxin Response Pathways in Floral Primordium Formation 
Science signaling  2013;6(270):ra23.
LEAFY is a transcription factor that acts as a master regulator of flowering and of flower development. It acts as a component of a switch that mediates the transition from the vegetative to the reproductive phase of plant development. Auxin is a plant hormone with many different roles in plant growth, including induction of new primordia of both leaves and flowers at the shoot apex. Here, we report that LEAFY acts in part by controlling the auxin response pathway in new primordia. Therefore, transcriptional master regulators of flower development and hormonal control of morphogenesis appear linked as interacting processes. We found that hormone perception not only controls, but is also controlled by, the transcriptional signals that create plant form.
doi:10.1126/scisignal.2003937
PMCID: PMC4122305  PMID: 23572147
12.  Attenuated Adiposopathy in Perivascular Adipose Tissue Compared to Subcutaneous Human Adipose Tissue 
American journal of surgery  2013;206(2):241-244.
Background
We hypothesized that human perivascular and subcutaneous adipose tissues hold distinct phenotypic signatures. We also evaluated the impact of clinical parameters on adipose phenotype. Our overall goal is to understand the determinants of adipose biology so that this tissue can be manipulated therapeutically to lessen peripheral vascular disease.
Methods
Perivascular and subcutaneous adipose tissues were collected from patients undergoing lower extremity amputation (n=27) and protein assayed for pro-inflammatory mediators (IL-6, IL-8, leptin, TNF-α MCP-1, resistin), athero-protective adiponectin, and the fibrinolysis inhibitor PAI-1.
Results
Leptin (2.7-fold, p=0.015), TNF-α (2.2-fold, p=0.013), MCP-1 (1.5-fold, p=0.047) and adiponectin (1.8-fold, p=0.004) were more abundant in subcutaneous versus perivascular adipose tissue. Age positively correlated with perivascular adipose tissue PAI-1 expression (β=0.64, p=0.042), and hyperlipidemia negatively correlated with perivascular adiponectin (β=−1.18, p=0.039).
Conclusions
Human perivascular and subcutaneous adipose tissues hold distinct phenotypic signatures. In amputation patients, the subcutaneous adipose tissue pro-inflammatory phenotype was relatively attenuated in perivascular adipose tissue.
doi:10.1016/j.amjsurg.2012.07.032
PMCID: PMC3688688  PMID: 23352378
Adipose; adipokine; perivascular
13.  Subscale Validation of the Neuropsychiatric Inventory Questionnaire (NPI-Q): Comparison of ADNI and NACC Cohorts 
Background
Neuropsychiatric symptoms (NPS) are common in Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD) and often measured using the Neuropsychiatric Inventory (NPI). Development of validated subscales that measure clinically meaningful symptom clusters would improve capacity for individualized treatment and assessment of treatment interventions. We report preliminary validation of three NPI Questionnaire (NPI-Q) subscales derived from examination of the existing exploratory literature and clinical knowledge.
Methods
The validity of subscales that assess Frontal, Agitation/Aggression, and Mood symptoms (based on NPI-Q-10 item scores) was ascertained by comparison of cross-sectional data from amnestic MCI and AD dementia cases from the National Alzheimer's Coordinating Center (NACC) and Alzheimer's Disease Neuroimaging Initiative (ADNI) databases. The statistical approach was confirmatory unrotated principal component analysis.
Results
ADNI contributed 103 MCI, 90 MCI-converters and 112 AD dementia cases while NACC had 1042, 763, and 3048. Baseline mean age was higher in NACC (74.6 vs 75.7). Patients in NACC were significantly more impaired at last visit on MMSE (mean scores 19.5 vs 22.4) and NPI-Q-10 (5.0 vs 4.3), as well as for each of the three subscales (NPI-Q-4-Frontal, NPI-Q-4-Agitation/Aggression, and NPI-Q-3-Mood than ADNI (at month 24). Medians were not different for Agitation/Aggression or Mood subscales, however. Each item on all scales contributed variance in PCA Pareto plots. All items in Factor (F) 1 for each scale projected in a positive direction on biplots (coherence), while F2 and F3 items showed more spatial separation (independence). Scale analyses showed remarkable similarities between ADNI and NACC cohorts for factor loadings and spatial patterns of item projections, though factor item identities varied somewhat, especially beyond F1.
Conclusions
The similar pattern of results across two cohorts of patients support the validity of these constructs. These subscales are worthy of further psychometric evaluation in patients with MCI and AD dementia and preliminary application in clinical settings.
doi:10.1016/j.jagp.2012.10.027
PMCID: PMC3913908  PMID: 23602309
Neuropsychiatric symptoms; Alzheimer's disease; Neuropsychiatric Inventory; subscales
14.  A sumoylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis 
Science (New York, N.Y.)  2011;335(6066):348-353.
Myc is an oncogenic transcription factor frequently dysregulated in human cancer. To identify pathways supporting the Myc oncogenic program, we employed a genome-wide RNAi screen for Myc-synthetic-lethal genes and uncovered a role for the SUMO-activating-enzyme (SAE1/2). Loss of SAE1/2 enzymatic activity drives synthetic lethality with Myc. Inactivation of SAE2 leads to mitotic catastrophe and cell death selectively upon Myc hyper-activation. Mechanistically, SAE2 inhibition switches a transcriptional subprogram of Myc from activated to repressed. A subset of these SUMOylation-dependent-Myc-switchers (SMS genes) is required for mitotic spindle function and to support the Myc oncogenic program. SAE2 is required for Myc-dependent tumor growth, and patient survival significantly correlates with SAE1/SAE2 levels in Myc-high tumors. These studies reveal a mitotic vulnerability of Myc-driven cancers, demonstrate that inhibiting sumoylation impairs Myc-dependent tumorigenesis, and suggest inhibiting SUMOylation may have therapeutic benefits for patients with Myc-driven cancer.
doi:10.1126/science.1212728
PMCID: PMC4059214  PMID: 22157079
15.  B and N isolate-doped graphitic carbon nanosheets from nitrogen-containing ion-exchanged resins for enhanced oxygen reduction 
Scientific Reports  2014;4:5184.
B,N-codoped carbon nanostructures (BNCS) can serve as alternative low-cost metal-free electrocatalysts for oxygen reduction reactions (ORR). However, the compensation effect between the p- (B atoms) and n-type (N atoms) dopants would make the covalent boron-nitride (BN) easily formed during the synthesis of BNCS, leading to a unsatisfactory ORR activity. Therefore, it has been challenging to develop facile and rapid synthetic strategies for highly active BNCS without forming the direct covalent BN. Here, a facile method is developed to prepare B and N isolate-doped graphitic nanosheets (BNGS) by using iron species for saving N element and simultaneous doping the B element from nitrogen-containing ion-exchanged resins (NR). The resulting BNGS exhibits much more onset potential (Eonset) compared with the B-doped graphitic carbon nanosheets (BGS), N-doped graphitic carbon nanosheets (NGS), as well as B,N-codoped disorder carbon (BNC). Moreover, the BNGS shows well methanol tolerance propery and excellent stability (a minimal loss of activity after 5,000 potential cycles) compared to that of commercial Pt/C catalyst. The goog performance for BNGS towards ORR is attributed to the synergistic effect between B and N, and the well electrons transport property of graphitic carbon in BNGS.
doi:10.1038/srep05184
PMCID: PMC4046170  PMID: 24898033
16.  STAT3 serine 727 phosphorylation influences clinical outcome in glioblastoma 
Besides STAT3 tyrosine 705 phosphorylation (pTyr705-STAT3), phosphorylation of STAT3 at serine 727 (pSer727-STAT3) is shown to contribute to tumorigenesis and be closely related with resistance to radiotherapy and chemotherapy in glioma, but there is currently no study regarding its relevance to prognosis in glioblastoma (GBM). Here, the expression of phosphorylated STAT3 was detected in tumor specimens from 88 patients with newly diagnosed GBM by immunohistochemistry, the Kaplan-Meier survival curve and COX proportional hazards regression model were applied to estimate its influences on progression-free survival (PFS) and overall survival (OS). Immunohistochemical assay showed elevated expression of pSer727-STAT3 in GBM compared with normal brain tissue. Univariate analysis indicated significant correlations of high percentage of pSer727-STAT3 positive tumor cells with shorter PFS (P = 0.006) and OS (P = 0.002). In multivariate analysis, high pSer727-STAT3 expression was demonstrated as an independent unfavorable prognostic indicator for PFS (HR 1.830, P = 0.022) and OS (HR 1.797, P = 0.040). And patients with high expression of both pTyr705-STAT3 and pSer727-STAT3 had a poorer prognosis compared with the remainder (P < 0.005). In conclusion, the high proportion of pSer727-STAT3 positive neoplastic cells in GBM is an independent unfavorable prognostic factor, and increased expression of both pTyr705-STAT3 and pSer727-STAT3 is predictive of poorer clinical outcome, thereby adding to the growing evidence that STAT3 inhibition may be a potential therapeutic strategy in glioblastoma.
PMCID: PMC4097241  PMID: 25031733
STAT3; serine; phosphorylation; prognosis; glioblastoma
17.  SHANK3 overexpression causes manic-like behavior with unique pharmacogenetic properties 
Nature  2013;503(7474):72-77.
Mutations in SHANK3 and large duplications of the region spanning SHANK3 both cause a spectrum of neuropsychiatric disorders, suggesting that proper SHANK3 dosage is critical for normal brain function. SHANK3 overexpression per se has not been established as a cause of human disorders, however, because 22q13 duplications involve several genes. Here we report that Shank3 transgenic mice modeling a human SHANK3 duplication exhibit manic-like behavior and seizures consistent with synaptic excitatory/inhibitory imbalance. We also identified two patients with hyperkinetic disorders carrying the smallest SHANK3-spanning duplications reported so far. These findings suggest SHANK3 overexpression causes a hyperkinetic neuropsychiatric disorder. To probe the mechanism underlying the phenotype, we generated a Shank3 in vivo interactome and found that Shank3 directly interacts with the Arp2/3 complex to increase F-actin levels in Shank3 transgenic mice. The mood-stabilizing drug valproate, but not lithium, rescues the manic-like behavior of Shank3 transgenic mice raising the possibility that this hyperkinetic disorder has a unique pharmacogenetic profile.
doi:10.1038/nature12630
PMCID: PMC3923348  PMID: 24153177
18.  Pre-Operative Diet Impacts the Adipose Tissue Response to Surgical Trauma 
Surgery  2012;153(4):584-593.
Background
Short-term changes in pre-operative nutrition can have profound effects on surgery related outcomes such as ischemia reperfusions injury in pre-clinical models. Dietary interventions that lend protection against stress in animal models (e.g. fasting, dietary restriction [DR]) impact adipose tissue quality/quantity. Adipose tissue holds high surgical relevance due to its anatomic location and high tissue volume, and it is ubiquitously traumatized during surgery. Yet the response of adipose tissue to trauma under clinically relevant circumstances including dietary status remains poorly defined. We hypothesized that pre-operative diet alters the adipose tissue response to surgical trauma.
Methods
A novel mouse model of adipose tissue surgical trauma was employed. Dietary conditions (diet induced obesity [DIO], pre-operative DR) were modulated prior to application of surgical adipose tissue trauma in the context of clinically common scenarios (different ages, simulated bacterial wound contamination). Local/distant adipose tissue phenotypic responses were measured as represented by gene expression of inflammatory, tissue remodeling/growth, and metabolic markers.
Results
Surgical trauma had a profound effect on adipose tissue phenotype at the site of trauma. Milder but significant distal effects on non-traumatized adipose tissue were also observed. DIO exacerbated the inflammatory aspects of this response, and pre-operative DR tended to reverse these changes. Age and LPS-simulated bacterial contamination also impacted the adipose tissue response to trauma, with young adult animals and LPS treatment exacerbating the proinflammatory response.
Conclusions
Surgical trauma dramatically impacts both local and distal adipose tissue biology. Short-term pre-operative DR may offer a strategy to attenuate this response.
doi:10.1016/j.surg.2012.11.001
PMCID: PMC3603342  PMID: 23274098
19.  Inflammatory “Adiposopathy” in Major Amputation Patients 
Annals of vascular surgery  2013;27(3):346-352.
Background
Much ado has been made about obesity’s health impact, largely founded on simple patient weight and circulating adipose-derived mediator levels. Paradoxically, a “healthy obese” state exists, but substantial knowledge gaps also exist regarding human adipose-phenotype determinants. Surgical major amputation (AMP) patients are the “sickest-of-the-sick”. Conversely, elective knee-replacement (TKR) is reserved for patients who expect continued health and longevity. To delineate human adipose biology variability and clinical determinants, we studied fresh subcutaneous adipose from AMP patients, using TKR patients as controls. We hypothesized that AMP patients would display a pro-inflammatory adipokine signature, and that certain clinical conditions (diabetes, hypertension, hyperlipidemia, high BMI, uremia) would independently drive elevated adipose inflammation.
Methods
AMP (n=29) and TKR (n=20) adipose and clinical data were collected prospectively, and protein was isolated and analyzed for eight adipose-related mediators. Statistical analyses included Wilcoxon-rank sum, Fischer’s exact and multiple linear-regression modeling of clinical parameter predictors of mediator expression.
Results
IL-6, IL-8, leptin, resistin, and PAI-1 were differentially expressed (up to 200-fold) between AMP/TKR cohorts. Key clinical parameters which associated with protein levels of adipose-phenotype included age, sex, hypertension, hyperlipidemia, congestive heart failure, cerebrovascular disease, renal disease, and warfarin, statin, and insulin use, with simple BMI failing to be predictive.
Conclusions
AMP-patients display adiposopathy, with a pro-inflammatory adipose-phenotypic signature compared to TKR-controls. BMI fails to predict phenotype, yet other clinical conditions such as age, hyperlipidemia, and renal insufficiency do drive adipokine expression. Understanding human adipose-phenotypic determinants stands as a fundamental priority when future studies dissect the interplay between adipose biology and surgical diseases/outcomes.
doi:10.1016/j.avsg.2012.07.017
PMCID: PMC3603344  PMID: 23498310
20.  Evolutionary Interrogation of Human Biology in Well-Annotated Genomic Framework of Rhesus Macaque 
Molecular Biology and Evolution  2014;31(5):1309-1324.
With genome sequence and composition highly analogous to human, rhesus macaque represents a unique reference for evolutionary studies of human biology. Here, we developed a comprehensive genomic framework of rhesus macaque, the RhesusBase2, for evolutionary interrogation of human genes and the associated regulations. A total of 1,667 next-generation sequencing (NGS) data sets were processed, integrated, and evaluated, generating 51.2 million new functional annotation records. With extensive NGS annotations, RhesusBase2 refined the fine-scale structures in 30% of the macaque Ensembl transcripts, reporting an accurate, up-to-date set of macaque gene models. On the basis of these annotations and accurate macaque gene models, we further developed an NGS-oriented Molecular Evolution Gateway to access and visualize macaque annotations in reference to human orthologous genes and associated regulations (www.rhesusbase.org/molEvo). We highlighted the application of this well-annotated genomic framework in generating hypothetical link of human-biased regulations to human-specific traits, by using mechanistic characterization of the DIEXF gene as an example that provides novel clues to the understanding of digestive system reduction in human evolution. On a global scale, we also identified a catalog of 9,295 human-biased regulatory events, which may represent novel elements that have a substantial impact on shaping human transcriptome and possibly underpin recent human phenotypic evolution. Taken together, we provide an NGS data-driven, information-rich framework that will broadly benefit genomics research in general and serves as an important resource for in-depth evolutionary studies of human biology.
doi:10.1093/molbev/msu084
PMCID: PMC3995340  PMID: 24577841
human evolution; rhesus macaque; human-specific trait; next-generation sequencing; human regulation; RhesusBase
21.  2-((E)-{4-[Bis(4-eth­oxy­phen­yl)amino]­phen­yl}imino­meth­yl)phenol 
In the title Schiff base mol­ecule, C29H28N2O3, the three terminal benzene rings are twisted by 73.84 (15), 81.25 (16) and 12.1 (2)° with respect to the central benzene ring. An intra­molecular O—H⋯N hydrogen bond occurs. In the crystal, mol­ecules are linked via weak C—H⋯π inter­actions into a three-dimensional supra­molecular architecture.
doi:10.1107/S1600536814003201
PMCID: PMC3998452  PMID: 24765014
22.  Perivascular innate immune events modulate early murine vein graft adaptations 
Journal of vascular surgery  2012;57(2):486-492.e2.
Objective
Innate immunity drives numerous cardiovascular pathologies. Vein bypass grafting procedures are frequently accompanied by low-grade wound contamination. We hypothesized that a peri-graft innate immune challenge, via an outside-in route, augments inflammatory responses, which subsequently drive a component of negative vein graft wall adaptations; moreover, adipose tissue mediates this immune response.
Methods
The inferior vena cava from a donor mouse was implanted into the common carotid artery of a recipient mouse utilizing a validated cuff technique (9-week-old male C57BL/6J mice). Slow-release low-dose (5 μg) lipopolysaccharide (LPS) (n = 9) or vehicle (n = 9) was applied peri-graft; morphologic analysis was completed (day 28). In parallel, vein-grafted mice received peri-graft LPS (n = 12), distant subcutaneous LPS (n = 6), or vehicle (n = 12), then day-1 and -3 harvest of grafts and adipose tissue for cytokines and toll-like receptor (TLR) signaling mRNA expression (qRT-PCR).
Results
All recipient mice survived, and all vein grafts were patent. Acute low-dose local LPS challenge enhanced vein graft lumen loss (P = .04) and tended to augment intimal hyperplasia (P = .06). The surgical trauma of vein grafting universally upregulated key pro- and anti-inflammatory mediators within the day-1 graft wall, but varied on TLR signaling gene expression. Local and distant LPS accentuated these patterns until at least postoperative day 3. LPS challenge enhanced the inflammatory response in adipose tissue (locally > distantly); local LPS upregulated adipose TLR-4 dramatically.
Conclusions
Perivascular and distant inflammatory challenges potentiate the magnitude and duration of inflammatory responses in the early vein graft wall, negatively modulating wall adaptations, and thus, potentially contribute to vein graft failure. Furthermore, surgery activates innate immunity in adipose tissue, which is augmented (regionally > systemically) by LPS. Modulation of these local and distant inflammatory signaling networks stands as a potential strategy to enhance the durability of vascular interventions such as vein grafts. (J Vasc Surg 2013;57:486-92.)
Clinical Relevance
Vein graft failure is traditionally considered as a process driven by luminal hemodynamic forces and endothelial injury. We report that the “outside-in” mechanism of local perivascular and distant inflammatory challenges potentiate the magnitude and duration of inflammatory responses in the early vein graft wall, negatively modulating wall adaptations, and thus potentially contribute to vein graft failure. Modulation of these inflammatory signaling networks (eg, extension of antibiotic administration beyond standard wound prophylaxis regimens) stands as a potential strategy to enhance the durability of vascular interventions such as vein grafts.
doi:10.1016/j.jvs.2012.07.007
PMCID: PMC3603348  PMID: 23127978
23.  Locally Applied Leptin Induces Regional Aortic Wall Degeneration Preceding Aneurysm Formation in ApoE Deficient Mice 
Objective
Leptin promotes atherosclerosis and vessel wall remodeling. As abdominal aorta aneurysm (AAA) formation involves tissue remodeling, we hypothesized that local leptin synthesis initiates and promotes this process.
Methods and Results
Human surgical AAA walls were analyzed for antigen and mRNA levels of leptin and leptin receptor (ObR), as well as mRNA for matrix metalloproteinases (MMP)-9, and MMP-12. Leptin and ObR antigen were evident in all AAAs, and, leptin, MMP-9, and MMP-12 mRNA was increased relative to age-matched non-dilated controls. To simulate in vivo local leptin synthesis, ApoE-/- mice were subjected to a para-visceral peri-aortic application of low-dose leptin. Leptin-treated aortas exhibited decreased TGFβ and increased MMP-9 mRNA levels 5 days after surgery, and ObR mRNA was up-regulated by day 28. Serial ultrasonography demonstrated accelerated regional aortic diameter growth after 28 days, correlating with local medial degeneration, increased MMP-9, MMP-12 and peri-adventitial macrophage clustering. Furthermore, the combination of local peri-aortic leptin and systemic angiotensin II administration augmented medial MMP-9 synthesis and aortic aneurysm size.
Conclusions
Leptin is locally synthesized in human AAA wall. Para-visceral aortic leptin in ApoE-/- mice induces local medial degeneration, and augments angiotensin II-induced AAA, thus suggesting novel mechanistic links between leptin and AAA formation.
doi:10.1161/ATVBAHA.112.300543
PMCID: PMC3645930  PMID: 23220275
abdominal aortic aneurysm; leptin; vessel wall remodeling; transforming growth factor β; angiotensin II
24.  Lack of Interleukin-1 Signaling Results in Perturbed Early Vein Graft Wall Adaptations 
Surgery  2012;153(1):63-69.
Background
Vein grafts fail due to wall mal-adaptations to surgical injury and hemodynamic perturbations. Interleukin-1 signaling has emerged as an important mediator of the vascular response to trauma and hemodynamically induced vascular lesions. We therefore hypothesized that interleukin-1 signaling drives early vein graft wall adaptations.
Methods
Using interleukin-1 type I receptor knockout (IL-1RI−/−) and wild-type (B6129SF2/J) mice, we investigated morphologic changes 28 days after interposition isograft from donor inferior vena cava to recipient carotid artery, without (n=19) or with (n=13) outflow restriction. The impact of mouse strain on the response to vein arterialization was also evaluated between B6129SF2/J (n=18) and C57BL/6J (n=19) mice.
Results
No significant differences were observed in the traditional endpoints of intimal thickness and calculated luminal area, yet media+adventitia thickness of the vein graft wall of IL-1RI−/− mice was 44-52% smaller than wild-type mice, at the both proximal (P<.01, P<.01) and distal (P=.054, P<.01) portions of vein grafts, for both normal flow and low flow respectively. Compared with C57BL/6J strain, B6129SF2/J mice exhibited no difference in vein graft intimal thickness, but 2-fold higher media+adventitia thickness (P<.01).
Conclusion
When lacking interleukin-1 signaling, the vein graft wall adapts differently compared to the injured artery, showing typical intima hyperplasia though attenuated media+adventitia thickening. B6129SF2/J mice exhibit more media+adventitia response than C57BL/6J mice. The inflammatory networks that underlie the vein response to arterialization hold many roles in the adaptation of the total wall, thus the utility of anti-inflammatory approaches to extend the durability of vein grafts comes into question.
doi:10.1016/j.surg.2012.06.005
PMCID: PMC3488356  PMID: 22853857
interleukin-1; vein graft; wall adaptation; adventitia; mouse model
25.  Impact of Uremia on Human Adipose Tissue Phenotype 
The Journal of surgical research  2012;179(1):175-182.
Background
Recognition of adipose-related signaling in surgery is increasing, though direct interrogation of human adipose has been sparse. Few scenarios rival uremia for health impact. We hypothesized that adipose from uremic patients holds a relatively higher adipose derived hormone and pro-inflammatory adipokine signature; we simultaneously evaluated the impact of clinical parameters on adipose phenotype.
Materials and Methods
Adipose was harvested from surgical patients. Histology and protein analyses were completed for select mediators.
Results
In the 71 patient cohort, mean age=63.4y; 63.3% had diabetes, 49.2% had hyperlipidemia and 53.5% had coronary disease. Compared to non-uremic patients, uremic patients had 1/10th the levels of leptin (p<0.001), 1/3rd the levels of adiponectin (p<0.001), and 3-fold higher resistin (p<0.001). Females had 6-fold higher leptin, 1.5-fold higher adiponectin and 2-fold higher TNF-α but equivalent resistin. There were differences in mediators when stratified by age. In both the obese/non-obese strata, we observed a concordant pattern of association (magnitude/significance) of uremia and leptin/adiponectin/resistin. No differentials in other mediators emerged upon BMI stratification. Multiple regression analysis for leptin/adiponectin/resistin (with age/gender/uremia as independent variables) showed uremia as the highest independent predictor of all three mediators.
Conclusions
Advanced chronic kidney disease is associated with perturbations in adipose derived hormones (leptin/adiponectin/resistin). Adipose adiponectin and leptin (in contrast to reported plasma levels) was lower in uremic patients; there is an inverse correlation between adipose resistin and renal function. Compared with other clinical parameters including BMI, uremia dominates overall in determining adipose phenotype, highlighting the complex biologic interplay between uremia and adipose biology.
doi:10.1016/j.jss.2012.08.043
PMCID: PMC3581854  PMID: 23058473
Uremia; chronic kidney disease; adipose tissue; leptin; adiponectin; resistin

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